Our previous findings that (1) lymphokine activities including migration inhibitory factor (MIF), macrophage fusion factor (MFF) and macrophage chemotactic factor (MCF) be recovered from hypersensitivity lung granulomas; (2) intravenous administration of lymphokine-rich supernatants inhibits delayed skin reactions in guinea pigs immunized to unrelated antigens and (3) transient energy and detectable serum MIF activity are concurrently present during the initial stage of granuloma formation, provide the basis for studies proposed in this application. First, we will confirm and extend the preliminary observations that serum MIF and cutaneous energy are present in animals with pulmonary granulomas by determining the time course of their manifestation. We will then attempt to identify and characterize soluble factors responsible for cutaneous anergy in guinea pigs with hypersensitivity lung granulomas. To achieve this, passive transfer of anergy will be attempted by injecting serum from donors with granulomatous inflammatory lesions into immune animals with delayed hypersensitivity. Suppressive factors detected in sera of granulomatous animals will be physicochemically characterized and their relationship to circulating lymphokines will be examined. The passive transfer of anergy will also be attempted by injection of aqueous extracts of pulmonary granulomas to demonstrate that suppressive factor is directly produced in the granulomatous inflammatory lesions. Finally, an attempt will be made to identify the cell population(s) which are secreting factor(s) involved in the generation and maintenance of the anergic state. These studies will illuminate the underlying mechanism of anergy in granulomatous inflammation and the possible relationship between anergy and the in vivo regulation of lung granuloma formation.